P01AI174856

Immunologic and Virologic Basis of RhCMV/SIV Vaccine-Induced Replication Arrest Efficacy - Overall - Project Summary

Almost 2 decades ago, our research group began development of vaccine vectors based on the persistent SS-herpesvirus cytomegalovirus (CMV) because of the ability of CMV to elicit and indefinitely maintain high frequency, effector-differentiated T cell responses in diverse tissues.

Using the rhesus macaque (RM) model, we have demonstrated that not only do RhCMV/SIV vaccines provide superior efficacy against highly pathogenic SIV challenge than conventional SIV vaccines (in aggregate, 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection), this efficacy is of an entirely new pattern – early SIV replication arrest followed by eventual viral clearance – and is mediated by a novel immune response – MHC-E-restricted, effector memory-differentiated CD8+ T cells (which to date can only be elicited by CMV vectors with specific genetic programming).

We also know that the efficacy of MHC-E targeted CD8+ T cell responses is predicted by a whole blood transcriptomic signature featuring IL-15 signaling, but the mechanisms responsible for complete arrest and subsequent clearance of nascent SIV infection are not defined, including the questions of why MHC-E-restricted epitope recognition is required for efficacy, how these cells mediate replication arrest, and how the protective whole blood transcriptomic signature influences these unique effector responses.

In this program, we seek to both answer these questions and develop detailed criteria for "replication arrest" efficacy for guiding ongoing phase I/II clinical testing of human CMV/HIV vaccines. The proposed program will include the following 3 projects:

1) Immunologic and Virologic Characterization of RhCMV/SIV Vaccine-Mediated SIV "Replication Arrest" Efficacy
2) Characterization of the In Vivo T Cell (and Overall Immune) Interception of Primary SIV Infection after Vaccination with Differentially Response Programmed RhCMV/SIV Vectors (MHC-E- vs. MHC-II- vs. MHC-IA- Restricted) and a Conventional Prime-Boost SIV Vaccine (MHC-IA-Restricted)
3) Determination of the Minimal MHC-E-Restricted SIV Epitope Targeting Required for RhCMV/SIV Vaccine-Mediated SIV "Replication Arrest" Efficacy

These projects will be supported by 4 cores:
A) Administration
B) NHP
C) Advanced Spatial Analysis
D) 'Omics, Bioinformatics, and Data Management

In addition to guiding current and future clinical testing of HMCV/HIV vaccines, the understanding of the immunologic basis of "SIV replication arrest" efficacy and the role of MHC-E-restricted CD8+ T cells in this process will have broad implications for HIV cure approaches, as well as inform the use of MHC-E-restricted CD8+ T cells as universal (MHC haplotype independent) effectors for immunotherapies directed at other infectious diseases or cancer.

Oregon Health & Science University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Portland, Oregon 972393098 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-20-072)

Amendment Since initial award the total obligations have increased 320% from $4,983,192 to $20,945,705.